Dihydroimidazolium compounds



Patented Jan. 3, 1950 UNITED STATES PATENT 2,493,321,. DIHYDROIMIDAZOLIUM'COMPOUNDS Horace Shon1e..- Ind apo is, and E in It- Shepard, Beech Grove, Ind., assignors to. Eli Lilly and Comnahv, napo i In a o poration of Indi na No Drawing. Application July 19, 1946, 'iQLN 3 778 nwherein R and R2 are the same or diiferentali phatic hydrocarbon radicals each having. from l to 7 carbon atoms; R1 is an. aliphatic hydrocarbon residue having an average carbon content .ot 7

to 12 carbon atoms, the total. number of carbon atoms in R1 and the: larger of R and R2- being from 10 to 16, and the total number of carbon atoms in R, R1, and R2 being not greater than 1'7 X is an anion; and n is an integer irom 1 to 3 inclusive.

The R1 substituent has an average carbon content of '7 to 12 carbon atoms. Bythis we mean that the final composition is either one consisting of a single compound in which the R1 substituent is a radical having a single definite number of carbon atoms, 1. e., nonyl, undecyl, etc, or one consisting mainly of such a specific compound mixed with lesser amounts of corresponding compounds in which respectively the R1 substituents are close homologues of the single definite radical of that specific compound, the mixture being of such proportions that the average R1 carbon content is within the range of from about 7 to about 12; When the R1 substituent is derived from a pure compound, it will normally consist of a single specific radical. But it may be derived from a commercial product, as Ob:- tained by distillation or rectification, which consists mainly of a compound having a definite number of carbon atoms, but which may also contain close homologues of such compound, in which case the R1 substituent will comprise radicals of corresponding variation. For example, the R1 substituent may be derived from com:- mercial lauric acid, consisting mainly of lauric acid itself, with 12 carbon atoms, ,but also include ing alkyl acids of 10 and '14 carbon atoms, in

(Cl. zen-30956) which case he R1, s bsti n t e esu tin v p oduct wi l be ma l he litca oh u do v radical but will include some homologues such as e Q-o bonah i 3 a ad ca s. h ,R an 2 substi u n mav a o nt in su var at ons, but in most cases substantially pure starting.com,-- pound wi l be o v ent for these substit o a so that they may consistofdefinite radicals.

The compositions of matter of our invention may be: re arded as comprisingpositively charged dihydroimidazolium cations which aresubstituted aliph hyd a b n radical and whi h a com ine w h neg t v y oha goo a ions, h

liphatic h d a o g u s ma b Se ec ed rom st aight oh ih aturo d b an ed cha n saturated, and straight and, branched chain rm; saturated groups. The negatively charged anion ssoc a ed ith t e ihydr im do h at on may beany one of a number of negative ionssllch s,- fo xa pl t hl br m d ulieto, ce at o ph s ha e ion By a o xa np i and referring to the above structural formula,

when R is. a methyl group, R; a decylgroup, R 1.

a m hyl r up, a h i d ion, n 1' i 1' he compound is 1,3tdi nethyl-zsdecylrhiiadihydrm imidazolium chloride.

Iii-compou d o t s inve t on the s m oi the ar on-a ms contained in t o R stoop and the arge oi the t nd B2 groups ran es m L0 to 1o oarbon oms a d th 11 o th ca n to sinthe h ee ro p R331 and 32 doe not, xceed .l' he ioliow s e amp illus r te h se limit on e t and R12 each contain 1 oa bon ato R1 must. on a l ast .9 carbon t ms but mavo n h a num er up to its w limi f ca on toms; hen R o h o hs 6 a bo atoms a d 2 ontai 1 arbon atom R41. mu t c ntai .ot least it .o m nimum o 7 carbon atoms but not have more than 1'( carbon atoms; and when R1 contains 11 carbon tom n i er R or R2 may con a n-more than 5 carbon a om a d t th t oym ontain not more than 6 carbon atoms.

t sh ul b no d ha two isom ic fo ms o our c mpound ex t s mul n ou l becaus of a dynamic equilibrium. Thus,..compoundsof our invention may be represented by either of the following formulaez.

wherein R, R1, R2, X and n have the same significance as before. In Formula. A, the nitrogen at position 1 is tertiary, and the nitrogen at position 3 is quaternary. In Formula B, the nitrogen at position 1 is quaternary, and the nitrogen in position 3 is tertiary. In the specification and claims we employ for convenience Formula A, wherein R is attached to the tertiary nitrogen at position 1, and R2 is attached to the quaternary at postion 3. It will be understood that the two forms illustrated are to be regarded as equivalent and that both forms are to be considered as within the scope of this invention.

The compounds of this invention are distinguished by their effective bacteriostatic properties and their low hemolytic effect. Corresponding compounds in which the substituent in the R1 position has less than 7 carbon atoms have ineffective antibacterial action, and when the R, R1, and R2 substituents exceed the limits set forth in number of carbon atoms, the compounds have a large hemolytic effect and are correspondingly toxic.

In preparing the compounds of our invention, we may start with a dihydroimidazole containing the desired R1 substituent and one or the other of the R and R2 substituents. Such starting compound may be obtained from a dihydroimidazole containing the R1 substituent by reaction with an alkylating agent, to add the R or R2 substituent. Broadly, we may prepare the compounds embodying our invention by reacting such a starting compound with an alkylating agent such as, for example, the nitrates, sulfates, or halides of aliphatic hydrocarbons, to cause the addition of the remaining R or R2 substituent and to supply the anion X in the foregoing formulas. Preferably, and because of their ready availability, we employ the halidesby which we mean the chlorides, bromides, and iodides, and exclude the fluorides-and thus preferably form compounds in which the anion X is a halogen anionby which we mean a chloride, bromide, or iodide anion. The reaction is effected by mixing the substituted dihydroimidazole with the halide of the aliphatic hydrocarbon, allowing any spontaneous reaction to subside and subsequently heating the mixture to complete the reaction. The product may be purified by recrystallization or precipitation from suitable solvents or mixtures thereof. The theoretical amount of the aliphatic hydrocarbon halide may be used but it is preferable to use an excess to assure completion of the reaction. The reaction is conveniently, although not necessarily, carried out in a closed system thus eliminating any loss of the aliphatic hydrocarbon halide by volatilization. If desired, a suitable nonreactive solvent such as, for example, alcohol or ethyl acetate may be used as a vehicle during the reaction.

In preparing the compounds of our invention there may be used as starting material a mixture of similarly substituted dihydroimidazoles. Thus for example, the starting material may be a group of dihydroimidazoles wherein (referring to the above formulas) R1 is a mixture of aliphatic hydrocarbon radicals having an average of about 11 carbon atoms and consisting mainly of undecyl, but containing some higher and lower homologues in the range of about 9 to 15 carbon atoms (as derived, for example, from commercial lauric acid). Such starting material may be reacted with a halide of an aliphatic hydrocarbon such as methyl chloride to yield a mixture of the correspondingly substituted dihydroimidazolium '4 chlorides, consisting mainly of the compound in which the R1 substituent is undecyl and including in minor amounts compounds in which the R1 substituents are adjacent homologues of the undecyl radical.

It should be noted that the compounds of our invention comprising both of two isomeric forms as mentioned heretofore may be prepared by either of two routes. A dihydroimidazole substituted by the groups R and R1 may be alkylated with an Rz-containing alkylating agent. Likewise a dihydroimidazole substituted by the groups R1 and R2 may be alkylated by an R-containing alkylating agent. The same compound or mixture of compounds results when R, R1, and R2 are correspondingly identical in each alkylation reaction.

The compounds of our invention are salt-like and generally water-soluble, and consequently are subject to many of the ionic reactions which typify soluble inorganic salts. By anionic interchange reactions, one anion may be substituted for another. For example, by taking advantage of the lower solubility of a substituted dihydroimidazolium sulfate as compared with the solubility of the corresponding imidazolium chloride, the sulfate may be crystallized preferentially from a solution containing the dihydroimidazolium, sulfate and chloride ions. Illustrating another method of effecting this conversion, an aqueous solution of substituted dihydroimidazolium halide may be shaken with substantially insoluble silver sulfate, whereby the halide ion is removed as insoluble silver halide leaving in solution the dihydroimidazolium sulfate. Additionally, ionic interchange may be effected through the hydroxyl ion as an intermediate. Upon shaking an aqueous solution of a substituted dihydroimidazolium halide with silver oxide, there is formed the corresponding soluble dihydroimidadolium hydroxide and insoluble silver halide. Treatment of the soluble dihydroimidazolium hydroxide solution with the appropriate acid forms the desired dihydroimidazolium compound.

The following examples illustrate our invention:

Example 1 1,3-dimethyl-2-n-undecyl-4,5- dihydroimidazolium iodide represented by the formula may be prepared by reacting l-methyl-2-n-undecyl-4,5-dihydroimidazole with methyl iodide in the following manner: 60'

The 1-methyl-2-n-undecy14,5-dihydroimidazole used in the synthesis was prepared by refiuxing a mixture of 171 g. of ethyl laurate and g. of anhydrous ethylene diamine at 110-112 C. for 12 hours. The alcohol and excess ethylene diamine were removed by distillation and 172 g. of crude N-lauroyl ethylene diamine were obtained. A mixture of 162 g. of the crude N-lauroyl ethylene diamine and 187 g. of powdered calcium oxide was heated with stirring at 225 C. for 36 hours. The reaction mixture was cooled to room temperature and extracted three times with about 350 cc. of alcohol. The extract was distilled in vacuo and the reaction product, 2-nundecyl-4,5-dihydroimidazo1e, distilled at 180- 189 C./10 mm. It melted at 81-83 C. To 56.5 g.

55 .of the ;2 neundecylij-dihydroimidazqle were added 31.7 g. of dimethyl sulfate, the temperature of the reaction during the addition being maintained at about 85C. About 150 cc. of water were added and the reaction mixture stirred until the solid material had dissolved. An aqueous solution of 20 g. of 50 percent sodium hydroxide and about 150 cc. of butyl alcohol was added to the reaction mixture with agitation, the mixture filtered and the butyl alcohol layer separated. The reaction product, 1-methyl-2-n-undecyl-4,5- dihydroimidazole, was obtained by evaporation of the butyl alcohol and distillation of the residue at 167-172 C./6 mm.

- A cold mixture of 1.8 g. of l-methyl-Z-n-undecyl-4,5-dihydroimidazole and 1.7 g. of methyl iodide was sealed in atube. When the tube and its contents were warmed to about room temperature, a spontaneous reaction took place after which reaction the tube was heated for one hour at 100-110 C. The tube was then cooled to about room temperature and its contents dissolved in about 50 cc. of hot ethyl acetate. The hot solution was treated with decolorizing carbon, filtered and the filtrate cooled to about C., whereupon-crystals of 1,3-dimethyl-2-n-undecyl-4,5- dihydroimidazolium iodide separated. These were filtered off and redissolved in hot ethyl acetate from which solution, upon cooling to about 0 0., there separated substantially pure 1,3- dimethyl-2-nundecyl 4,5 dihydroimidazolium iodide which melted at about 120-122 C.

Example 2 l-n-amyl-2-n-undecyl-3-methyl- 4,5 dihydroimidazolium iodide represented by the formula may be prepared by reacting l-n-amyl-Z-n-undecyl-4,5-dihydroimidazole with methyl iodide as follows The 1-n-amyl-2-n-undecyl-4,5-dihydroimidazole used in the synthesis was prepared by treating the 2-n-undecyll,5-dihydroimidazole described in Example 1 with n-amyl chloride in the following manner: To 84.9 g. of Z-n-undecyl- 4,5-dihydroimidazole heated to 140-150 C. were added dropwise 21.7 g. of n-amyl chloride. The temperature of the reaction mixture was held at 14'7.-154 C. for a total of 16 hours. The reaction mixture was cooled to about 60 C. and a solution of 17.1 g. of 50 percent sodium hydroxide in a mixture of about 150 cc. of Water and 150 cc. of butyl alcohol was added to the reaction mixture with agitation and the agitation continued for one hour. The butyl alcohol layer was then separated and distilled to remove the butyl alcohol and water and the residue distilled at 145-180 C./ mm.

A cold mixture of 1.5 g. of l-n-amyl-2-n-undecyl-4,5-dihydroimidazole and 1.7 g. of methyl iodide was sealed in a tube. Upon Warming to about room temperature, the contents of the tube reacted spontaneously, after which reaction the tube was heated to 110 C. for one hour. Thetube was then cooled to about room temperature, its contents dissolved in about 40 cc. of hot ethyl acetate and the hot solution treated with decolorizing carbon and filtered. No precipitate was obtained upon cooling the filtrate to about 0 C. The filtratewas thereupon .treated with an excess .of petroleum ether which precipitated as an oil the 1-n-amyl-2-n-undecyl- 3 methyl 4,5 ,dihydroimidazolium iodide. The oil was purified by dissolving it in hot ethyl acetate, treating With decolorizing carbon, filtering and adding an excess of petroleum ether to reprecipitate the 1.-n-amyl- 2-n-undecyl-3- methyl 4,5 dihydroimidazolium iodide'as'an oilwhich was dried in a vacuum desiccator over sulfuric acid.

Example 3 1,3-dimethyl-2-nnonyl 4,,5 dihydroimidazolium iodide represented by the formula may be prepared by reacting 1-methyl-2-n-nonyl- 4,5-dihydroimidazole with methyl iodide as follows:

1-methyl-2-n-nonyl-4,5-dihydroimidazole was prepared from anhydrous ethylene diamine and ethyl decanoate in substantially the same manner as was prepared 1-methyl-2.-n-undecyl-4,5-dihydroimidazole described in Example 1.

A cold mixture of 1.5 g. of 1-methyl-2-n-nonyl- 4,5-dihydroimidazole and 1.7 g. of methyl iodide Was sealed in a tube. Upon warming to about room temperaturethe contents of the tube reacted spontaneously after which reaction the tube was heated to 110 C. for one hour. The tube was then cooled to about room temperature, its contents dissolved in about 50 cc. of a hot mixture of ethyl acetate and ethyl alcohol, and the solution treated withdecolorizing carbon. and filtered. Upon cooling the filtrate toabout 0 0., there separated a crystalline precipitate of 1,3 dimethyl-2-n-nonyl-4,5-dihydroimidazolium iodide which after recrystallization from ethyl acetate melted at about 50-5-1 C.

Example 4 1-methyl-2-n-nonyl-3 methallyl 4,5 dihydroimidazolium chloride represented by the formula H2C.-NCH3 o in may be prepared from 1-methyl-2-n-nonyl-4,5- dihydroimidazole andmethallyl chloride as fol-v lows:

A cold mixture of 1.8g. of 1-methyl-2--n-nonyl- 4,5-dihydroimidazole and 1.7 g. of methailyl chloride was sealed in a tube. The mixture upon warming to about room temperature reacted spontaneously after which reaction the tube was heated to -110 C. for one hour. The tube was then cooled to about room temperature, its contents dissolved in about 50 cc. of boiling ethyl acetate, and the solution treated with decolorizing carbon and filtered. Upon cooling the filtrate to about 0 C., no precipitate was obtained. The filtrate was thereupon treated with an excess of petroleum ether which precipitated as an oil the 1-methyl-2-n-nonyl-3 methallyl-4,5 dihydroimidazolium chloride. The oil was purified by dissolving it in hot ethyl acetate, treating with decolorizing carbon, filtering, and adding an excess of petroleum ether to reprecipitate the I-methyl- 2-n-nonyl-3-methallyl-4,5 dihydroimidazolium chloride as an oil which was then dried in a vacuum desiccator over sulfuric acid.

Example 'A mixture of substituted dihydroimidazolium chlorides represented by the following formula:

in which R and R2 are aliphatic hydrocarbon radicals each having from 1 to '7 carbon atoms, R1 is an aliphatic hydrocarbon residue having an average carbon content of 7 to 12 carbon atoms, the sum of the number of carbon atoms in R1 and the larger of R and R2 being from to 16, and the sum of the number of carbon atoms in R, R1, and R2 being not over 17; X is an anion; and n is an integer from 1 to 3 inclusive.

2. A composition of matter represented by the formula in which R and R2 are aliphatic hydrocarbon radicals each having from 1 to '7 carbon atoms and one of which is saturated, R1 is an aliphatic hydrocarbon residue having an average carbon content of 7 to 12 carbon atoms, the sum of the number of carbon atoms in R1 and the larger of R and R2 being from 10 to 16, and the sum of the number of carbon atoms in R, R1, and R2 being not over 17; X is an anion; and n is an integer from 1 to 3 inclusive.

3. A composition of matter represented by the formula in which R and R2 are aliphatic hydrocarbon radicals each having from 1 to '7 carbon atoms, R1 is an aliphatic hydrocarbon residue having an average carbon content of about 11 carbon atoms and consisting mainly of ll-carbon radicals, the sum of the number of carbon atoms in R, R1, and R2 being not over 17; X is an anion; and n is an integer from 1 to 3 inclusive.

4. A composition of matter represented by the formul Hg C--NC H;

wherein R1 is an aliphatic hydrocarbon residue derived from commercial lauric acid and having an average carbon content of 11 carbon atoms,

and Ha is a halogen anion other than fluorine.

5. 1,3-dimethyl-2-n-undecyl4,5 dihydroimidazolium iodide represented by the formula 6. 1,3-dimethyl-2-n-nonyl 4,5 dihydroimid azolium iodide represented by the formula HORACE A. SHONLE.

EDWIN R. SHEPARD.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,042,023 Schonhofer May 26, 1936 2,392,326 Kyrides Jan. 8, 1946 2,404,299 Kyrides July 16, 1946 2,404,300 Kyrides July 16, 1946 FOREIGN PATENTS Number Country Date 501,727 Great Britain Feb. 28, 1939 

1. A COMPOSITION OF MATTER REPRESENTED BY THE FORMULA 